PowerPoint Presentation CONCLUSION • The findings of this study indicate that in patients with PN, NAL-ER tablets, at a dose of 162 mg b.i.d., appear to have a measurable antipruritic effect for patients who successfully maintain the initial therapy for at least 10 weeks. • The significantly greater response rate for NAL-ER 162 mg patients who completed the full 10 weeks of double-blind treatment compared with placebo is consistent with a clinical benefit that requires compliance with the designated dosing schedule and duration. • Further evaluation of NAL-ER, including further elucidation of its underlying mechanism of action, is thus warranted in this difficult-to-treat disease, with a larger phase 2b/3 clinical trial currently evaluating the 162 mg b.i.d. dose. Efficacy and Safety of Oral Nalbuphine Extended Release in Prurigo Nodularis: Results of a Phase 2, Randomized, Controlled Trial with an Open-Label Extension Phase Elke Weisshaar1; Thomas R. Sciascia2; Sonja Ständer3 1Occupational Dermatology, Department of Dermatology, University Hospital, Heidelberg, Germany; 2Trevi Therapeutics, New Haven, CT, USA; 3Department of Dermatology and Center for Chronic Pruritus, University Hospital, Münster, Germany INTRODUCTION • Prurigo nodularis (PN) is a relatively rare, intensely pruritic dermatologic disease that develops from prolonged itching and scratching, with a high associated quality-of-life impact.1 • The current guidelines for treating PN are based on empirical observations and single, randomized, controlled trials.2,3,4 • Therapies such as calcineurin inhibitors, topical steroids, and systemic antihistamines have limited data to support their use. • The synthetic opioid nalbuphine, a dual-acting µ antagonist and  agonist, has shown efficacy in morphine-induced pruritus and uremic pruritus,5,6 but an evaluation of the efficacy and safety of nalbuphine in PN is currently lacking. METHODS • Patients with moderate-to-severe PN (pruritus duration ≥ 6 weeks) were randomized 1:1:1 to receive either NAL-ER 81 mg or 162 mg tablets twice-daily (b.i.d.), or placebo for 8 weeks of stable dosing following a 2-week titration period (for dose-escalation from 30 mg once-daily to the assigned target dose). • Itch scores based on Worst Itch (WI) and average itch Numerical Rating Scale (NRS) with 24-hour recall were collected daily by an electronic diary (DIARYpro®). • The primary efficacy endpoint was the proportion of patients with a ≥ 30% reduction in 7-day mean WI-NRS from baseline to Week 10/last observation. • The primary safety endpoint was the incidence of opioid-type adverse events of nausea, vomiting, constipation, somnolence, sedation, dizziness, and vertigo in each treatment group. RESULTS, continued RESULTS, continued • Treatment-emergent adverse events (TEAEs) occurred predominantly during the titration period in both studies. During double-blind, stable-dose treatment that followed titration, TEAE incidence was similar for both active treatment arms and placebo (Table 2). • Common TEAEs were nausea, dizziness, headache, and fatigue; the majority of these events were also considered treatment-related in all 3 arms (Table 2). • In the extension study, 34 patients reported 154 TEAEs, including 26 patients with ≥ 1 drug-related TEAE. TEAEs included nausea (n = 9; 25.0%), and dizziness and fatigue (n = 8 for each; 22.2%). REFERENCES 1. Ständer HF, et al. J Am Acad Dermatol. 2020;82:460-68. 2. Tsianakas A, et al. Curr Probl Dermatol. 2016;50:94-101. 3. Weisshaar E, et al. Acta Derm Venereol. 2019;99:469-506. 4. Ständer S, et al. Itch. 2020; submitted. 5. Kjellberg F, Tramèr MR. Eur J Anaesthesiol. 2001;18:346-57. 6. Mathur VS, et al. Am J Nephrol. 2017;46:450-8. Presented at the 2021 Winter Clinical Dermatology Conference–Hawaii® OBJECTIVE • To evaluate the efficacy and safety of oral nalbuphine extended release (NAL-ER) tablets in a phase 2, multicenter, randomized, double-blind, placebo-controlled trial with an open-label extension phase. ACKNOWLEDGMENT This study was funded by Trevi Therapeutics. The authors received writing/editorial support in the preparation of this poster provided by Excerpta Medica, funded by Trevi Therapeutics. CONFLICTS OF INTEREST EW is an investigator in clinical trials for Kiniksa, Menlo Therapeutics, and Trevi Therapeutics. TRS is an employee of Trevi Therapeutics. SST is an investigator for Dermasence, Galderma, Kiniksa, Menlo Therapeutics, Trevi Therapeutics, Novartis, Sanofi, and Vanda Therapeutics; a consultant and/or advisory board member for Almirall, Bayer, Beiersdorf, Bellus Health, Bionorica, Cara Therapeutics, Celgene, Clexio, DS Biopharma, Galderma, Kiniksa, Lilly, Menlo Therapeutics, Novartis, Pfizer, Sanofi, and Trevi Therapeutics. Table 2. Treatment-emergent adverse events (safety population) Adverse event, n (%) NAL-ER Placebo (n = 22)81 mg (n = 22) 162 mg (n = 18) TEAE 17 (77.3) 16 (88.9) 14 (63.6) Serious TEAE 1 (4.5) 0 (0) 1 (4.5) Related TEAE 12 (54.5) 13 (72.2) 8 (36.4) TEAE onset during Titration period 16 (72.7) 13 (72.2) 10 (45.5) Fixed dose period 8 (36.4) 8 (44.4) 8 (36.4) Washout/safety 6 (27.3) 6 (33.3) 4 (18.2) TEAE with > 15% incidence overall by System Organ Class / Preferred Term Gastrointestinal disorders Nausea 4 (18.2) 7 (38.9) 1 (4.5) General disorders and administration-site conditions Fatigue 5 (22.7) 2 (11.1) 0 Nervous system disorders Dizziness 5 (22.7) 7 (38.9) 1 (4.5) Headache 6 (27.3) 5 (27.8) 2 (9.1) Table 1. Primary and secondary efficacy outcomes (mITT) of responders Endpoints, n/N (%) NAL-ER Placebo 81 mg 162 mg Primary endpoints ≥ 30% reduction in 7-day WI intensity NRS vs baseline Last observation 6/22 (27.3) 8/18 (44.4) 8/22 (36.4) Completers 6/18 (33.3) 8/12 (66.7) 8/20 (40.0) ≥ 50% reduction in 7-day WI intensity NRS vs baseline Last observation 3/22 (13.6) 6/18 (33.3) 4/22 (18.2) Completers 3/18 (16.7) 6/12 (50.0)* 4/20 (20.0) Secondary endpoints ≥ 30% reduction in 7-day average itch intensity NRS vs baseline Last observation 11/22 (50.0) 11/18 (61.1) 9/22 (40.9) Completers 11/18 (61.1) 10/12 (83.3)* 8/20 (40.0) ≥ 50% reduction in 7-day average itch intensity NRS vs baseline Last observation 8/22 (36.4) 6/18 (33.3) 4/22 (18.2) Completers 8/18 (44.4) 6/12 (50.0)* 4/20 (20.0) Study completers were analyzed as a subset of all mITT. Completers are patients who completed Week 10 of the study and attended Visit 5. *p ≤ 0.05 vs placebo. mITT, modified intent-to-treat. RESULTS • Of 62 treated patients, 50 completed 10 weeks of treatment. The primary efficacy endpoint of percentage of responders with ≥ 30% reduction from baseline in 7-day WI intensity was not significant for the primary modified intent-to-treat analysis but, was significant for NAL-ER 162 mg (66.7%) compared with placebo (40.0%; p = 0.026) among completers (Table 1).